Neuro & Immuno Tox

sihirlifil's version from 2018-02-28 10:56


Question Answer
Neurotoxicology =Substance induced dysfunction of the nervous system
Types of neurotoxAcute, chronic, delayed, developmental
Direct or indirect
Central or peripheral
Reversible or irreversible
E.g. of delayed neurotoxOrganophosphates
Is neurotox in the brain more likely reversible or irreversible?Irreversible
(tangent) What's the MDR-1 gene, why is it importantPoint mutation causes normal doses of Ivermectin to become toxic in certain breeds
Affects GABA receptors in parasite (Benzodiazepine antags can relieve some symptoms of tox)
What's this picture saying?
The right is the blood-brain barrier: glial cells, tight junctions, ABC transporters (transport substances back out as soon as they are absorbed, protects brain against chemicals)
PNS vs. CNS toxicity depends onThe drug
How are ion channels involved in toxicity?Toxins interact with ion channels --> interfere with action potential
Who is this and why do we care
Puffer fish, related to saxitoxin found in paralytic shellfish poisoning
How does saxitoxin work?(pufferfish one) High affinity block of the voltage-gated sodium channels
What does saxitoxin cause?Tingling, numbness, paralysis
40% of victims die (annually 125 globally)
What is myotonia? caused by?Ion channel defects: neuromuscular defect resulting in slow muscle relaxation after getting tense
Caused by mutation in the chloride channel --> reduced chloride conductance in the muscle membrane. Evoked by stress, heat, cold, fear, sudden exercise (think of the fainting goats! also affects humans, dogs, mice)
What are the patterns of neurotoxic injury?Neuronopathy
Interruption of the process of neurotransmission
What is A?
Normal neuron
What is B?
Neuronopathy resulting from the death of the ENTIRE NEURON
What is C?
Axonopathy where the AXON is the primary site of injury. The axon degenerates, neurons only show chromatolysis
What kind of nerves do axonopathies typically affect? Longer axons
What is D?
Myelinopathy resulting from disruption of myelin, or from selective injury to the myelinating cells
WHat is E?
Interruption from the process of neurotransmission
(patterns of neurotox) How is neurotransmission interrupted?Na channel block, local anesthetics, inhibition of Ca channels
Types of neuropathy (3)Sensory
Types of neuropathy: effects of sensoryAlters sensation (mind blown!) & may cause symptoms of tingling, pain, numbness or weakness of the limbs in affected individuals
Types of neuropathy: effects of motorAffects strength & movement, and may cause immobility or weakness of the limbs in affected individuals
Types of neuropathy: effects of autonomicAffects the control of smooth muscle in the body, such as the GI tract, bladder, CVS
Neuropathy vs. neuronopathyNeuropathy is the BROAD term used to describe any disease that affects the peripheral nervous system. This includes disorders that affect the cell body of the neurons & neuronopathies (more umbrella term). So a neuronopathy is a subgroup of PNS disorders (type of polyneuropathy) involving the destruction of specific neurons in the that area (sensory aka ganglionopathy, motor, autonomic) (remember neuronopathy is death of the ENTIRE NEURON)
Axonopathy vs. neuronopathy (basic)Axonopathy: PROXIMAL part of the nerve may survive. Neuropathy: ENTIRE NEURON DIES
How does an axonopathy progress?Distal degeneration of the axon and Schwann cells occurs when axonal transport is interrupted. The proximal part of the axon and the neuron soma (body) may survive in distal axonopathy. BUT injury of the neuron cell body leads to complete degeneration of soma, axon, and associated Schwann cells (=neuronopathy) (pretty much as long as the cell body is ok, the proximal part of the nerve can survive while everything distal to the problem dies)

dumb charts

Question Answer
Stuff that affects the ENTIRE neuronAluminum
Carbon monoxide

(Entire) Chloramphenicol: neurologic findings?Optic neuritis, peripheral neuropathy
Neuronal loss (retina), axonal degeneration (PNS)
(Entire) Doxorubicin: neurologic findings?Progressive ataxia
Degen of dorsal root ganglion cells
(Entire) Ethanol: neurologic findings?Mental retardation, hearing deficits (prenatal exposure)
Microcephaly, cerebral malformations
(Entire) Phenytoin: neurologic findings?Nystagmus, ataxia, dizziness
Degen of Purkinje cells (cerebellum)
(Entire) Streptomycin: neurologic findings?Hearing loss
Degen of organ of Corti
Stuff that affects the AXONAcrylamide
(Axon) Metronidazole: neurological findings?Sensory,peripherall neuropathy, ataxia, seizures
Axon degen, mostly affecting MYELINATED fibers, lesions of cerebellar nuclei
(Axon) Organophosphates: neurological findings?Abdominal pain (lol), delayed peripheral neruopathy
Axonal degen
(MOA of organophosphates)(Block ACh esterase)
Stuff that affects TRANSMISSIONAmphetamine
Muscarine (shrooms)
Excitatory amino acids
(Transmission) Atropine: neurological findings?Restlessness, irritability, hallucinations
Block cholinergic receptors
(Transmission) Excitatory AA: neurological findings?Hypoxia, epilepsy, neurodegen dz
Opens gluatmate-dependent ion channels --> neuronal swelling, cell death


Question Answer
What's going on with this chart?
Top: adverse effects of immunostimulation (allergies)
Middle: Normal range of immune response
Bottom: Adverse effects of immunosuppression
explain some stuff
HYPERSENSITIVITY: can be due to penicillin, other antibiotics, NSAIDs. TISSUE INJURY: cytokine storm! continuous exposure of immune system to active agent --> continuous production of cytokines --> multi organ failure --> SIRS. IMMUNODEPRESSION: chemo drugs, steroids. when immune system depressed e.g. from cytostatic drugs (chemo): BM & other rapidly dividing cells are affected --> decr WBC --> no recognition of pathogens --> no creation of cytokines. Vaccine efficacy can also decrease (with glucocorticoids and mycotoxins too) (sorry for this clusterfuck)
How do cytokines contribute to immune stimulation?No negative feedback because continuous production of pro-inflammatory cytokines --> tissue damage
What causes drug allergy/immune-mediated liver pathology?Pharmaceuticals
Environmental pollutants
Occupational chemicals
What causes contact allergy?Allergic contact dermatitis
Occupational chemicals
Environmental pollutants
Chemicals at home
What causes airway allergy (asthma)?In/outdoor air pollution
Respiratory allergens (...)
What causes food allergy?Genetically modified food
New (artificial) protein sources
Adverse reactions to vet drugs: HORSES?Procaine benzylpenicillin
Na/K benzylpenicillin
Adverse reactions to vet drugs: CATTLE & SWINE?Antimicrobial agents
Adverse reactions to vet drugs: DOGS?NSAIDs
alpha-2 agonists
What happened here?
Immune reaction to a live vax. Extensive skin necrosis with sharp margins (he said pyrexia 4h after too)
What happened here?
Allergic dermatitis from Sulfonamide toxicity
Metabolism mediated (oxidative metabolite), T-cell mediated.
Sulfonamides: Potential problems for dogs?Fever, arthropathy, PLE, blood dsycrasia, skin (usually idiosyncratic)
Immunotherapy: Induction of immune toleranceRepeated dosing of allergen in allergic individuals (very small amounts, increase as tolerance develops)
Risk of induction of immune tolerance (therapy)Systemic reactions to the allergen: anaphylaxis
Immunotherapy: Modulation of the immune system- how?Reversing the Th2-biased response
Possible triggers: bacterial & viral infections
Th1 response: IFN-gamma production
Example of immune therapyAtopic dogs treated with peanut & heat-killed Listeria monocytogenes
Predisposing factors for allergy: Example?Insect bite hypersensitivity in horses: Culicoides species are rare in Iceland, and so the horse doesn't develop a Th2 response. When imported, develop hypersensitivity b/c they aren't used to being exposed to culicoides. If you breed the mare, see less hypersensitivity = more balanced immune response developed
Protection due to tolerance induction in early life. Maternal IgE: immune-mediated tolerance (IGF-beta & IL-10)
Low incidence of viral infections (EHV-1 & flu): viral infections induce a Th1 response!
Adults are dewormed after export (helminths: induced IgE protects against allergens induced IgE)